Recent high profile reports have identified the enigmatic hippocampal area CA2 as being at the center of an entirely new hippocampal circuit that is essential for social learning linked to autism and schizophrenia. Unlike the well-understood trisynaptic (dentate gyrus (DG)-CA3-CA1) hippocampal circuit, very little is known about area CA2. Previously, this brain region had been indirectly implicated in the autism/bipolar spectrum of disorders and schizophrenia. However, these new reports demonstrating CA2's essential role in social learning provide a compelling novel link between this brain region with autism/bipolar disorders and schizophrenia. Therefore, understanding signaling proteins and pathways in CA2 neurons offers an exciting new opportunity for the development of novel therapeutic tools to treat these devastating and vexing diseases. We have shown that the brain protein RGS14 is expressed in pyramidal neurons of hippocampal region CA2 in adult mouse and humans. RGS14 is an unusual scaffold/effector protein that integrates G protein, MAPkinase, and Ca++/CaM signaling pathways essential for synaptic plasticity. We recently discovered that RGS14 is critically important as a natural suppressor of synaptic plasticity in CA2 neurons but not CA1. Mice lacking RGS14 (RGS14-KO) exhibit a marked and unexpected enhancement of long-term potentiation (LTP) in CA2 neurons and in the acquisition of hippocampal-based spatial learning and memory, with no differences in other behaviors. These findings highlight the importance of understanding the molecular mechanism(s) whereby RGS14 regulates synaptic plasticity in its natural host CA2 hippocampal neurons. To date, very little is known about signaling proteins/pathways in CA2 neurons. Furthermore, our understanding of RGS14 signaling functions is based largely on binding interactions of recombinant RGS14 and partners in non-native expression systems. Based on these findings, our working hypothesis is that RGS14 is a central nexus that regulates signaling pathways essential for synaptic function and plasticity. Yet nothing is known about natural binding partners of native RGS14, and the signaling pathways it engages within its natural host CA2 neurons. Consistent with this idea, our preliminary studies show that native RGS14 exists as a high molecular weight protein complex and binds unidentified partners from brain. The goal of these studies is to define novel signaling pathways in RGS14-expressing CA2 hippocampal neurons for future study, and the specific signaling pathways that native RGS14 engages to regulate synaptic plasticity. AIM 1: Determine the cell transcriptome and proteome of RGS14-expressing CA2 hippocampal neurons and CA2-specific signaling pathways using bioinfomatics analysis. AIM 2: Identify natural binding partners of native RGS14 from brain (wild type vs RGS14-KO). AIM 3: Determine roles for newly identified CA2-specific receptor pathways in regulating LTP in CA2 neurons of hippocampal slice preparations from wild type and RGS14-KO mice.